Methods of treating disease-induced ataxia and non-ataxic imbalance

ABSTRACT

Methods for treatment of disease-induced ataxia and non-ataxic imbalance are disclosed. The methods involve treating a patient with a compound having nicotinic acetylcholine receptor activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. ProvisionalApplication Ser. No. 61/041,069, filed on Mar. 31, 2008; Ser. No.61/041,408, filed on Apr. 1, 2008; Ser. No. 61/043,522, filed on Apr. 9,2008; Ser. No. 61/056,173, filed on May 27, 2008; and Ser. No.61/076,343, filed on Jun. 27, 2008, each of which is hereby incorporatedby reference herein in its entirety.

BACKGROUND

The present disclosure generally relates to methods for treatment ofdisease-induced ataxia and non-ataxic imbalance. These symptoms can betreated in a patient by administering to the patient a compound havingnicotinic acetylcholine receptor activity.

The role of nicotine on the human cerebellum is unclear. Nicotinicreceptors appear responsible for disorders like Alzheimer's disease,anxiety, drug addition, epilepsy, Parkinson's Disease, schizophrenia,and Tourette's Syndrome. A report by Pereira et al. (NeuroReport 2001,8, 1223-1226) showed that nicotine was associated with posturalimbalance in non-smokers and occasionally in smokers, and alsocontributed to nystagmus and body sway (Spillane J D, Br. Med. J. 1955,2: 1345, 1345-1351). Prenatal or neonatal nicotine exposure is thoughtto interfere with brain development in both human and animal studies. Infact, nicotine crosses the placenta (Al-Rejaie et al., Alcohol Clin.Exp. Res. 2006, 30(7), 1223-33). Smoking during pregnancy has beenassociated with miscarriage, sudden infant death syndrome (SIDS), andneurobehavioral disturbances including hyperactivity, depression, andanxiety (Smith et al., Brain Res. 2006, 1115(1), 16-25; Katz et al., J.Physiol. 1967, 138, 63-80). One study found that concurrent exposure ofthe human brain to alcohol and nicotine during a brain growth spurtsreduced the total number of Purkinje cells (Arneric et al., BiochemicalPharmacology 2007, 74, 1092-1101). Another study compared the expressionof nicotinic and muscarinic acetylcholine receptors in the firsttrimester in the pons, medulla oblongata, and cerebellum in 5-12 weekgestation abortus of smoking and non-smoking women (Katz et al., J.Physiol. 1967, supra). The gene expression pattern of both α4 and α7nicotinic receptor subunits in these regions was altered after smoking.These findings suggest that early prenatal nicotine exposure affects thenormal developmental pattern of the human fetal cholinergic system.

Unlike nicotine, selective activation of nicotinic acetylcholinereceptors, such as the α4β2 nicotinic acetylcholine receptor, mayimprove ataxia (Al-Rejaie et al., Alcohol Clin. Exp. Res. 2006, supra).Partial agonism of this receptor has been shown to decrease ataxia inanimal models that was induced by alcohol (Al-Rejaie et al., AlcoholClin. Exp. Res. 2006, supra) or tetrahydrocannabinoid (Smith et al.,Brain Res. 2006, supra). Nicotinic acetylcholine receptors are rapidlydesensitized by up-regulation (Katz et al., J. Physiol. 1967, supra),and partial α₄β₂ nicotinic acetylcholine receptors agonists likevarenicline may paradoxically behave as antagonists rather than agonists(Arneric et al., Biochemical Pharmacology 2007, supra).

The α₄β₂ receptor in the mammalian brain has been linked to reward,tolerance and sensitization of nicotine (West et al., Psychopharmacology2008; 197(3):371-7). In vivo studies of nicotinic acetylcholinereceptors found an increased binding of [3H]nicotine in several areas ofthe brain in smokers, with prominent regional differences ofdistribution volumes in the cerebellum and brain stem, with an increaseduptake in smokers compared to non-smokers (West et al.,Psychopharmacology 2008, supra).

Varenicline is a recently-developed drug structurally based on cytisine,used as a prescription drug to combat smoking addition. Varenicline is anicotinic receptor agonist, acting as a partial agonist of manynicotinic acetylcholine receptors, including the α₄β₂ subtype, found inthe cerebellum (Schmitz-Hübsch et al., Neurology 2006, supra). Recentreports also show varenicline acts as a potent, full agonist of the α₇receptor subtype (K. Minalak, et al., Molec. Pharm., 70(3):801-805(2006)). As noted above, nicotinic acetylcholine receptors rapidlydesensitize by up-regulation of the active agent leading to thehypothesis that certain agents may act on these receptors functionallyas antagonists, rather than as agonists.

Multiple neurodegenerative diseases and toxic exposures can lead to theprogressive loss of the ability to coordinate movements. Symptoms ofthese physically devastating diseases and conditions include ataxia,imbalance, and sensory abnormalities. Ataxia and imbalance caused by,among other things, cerebellar disease, progressive supranuclear palsy(PSP) and atypical parkinonsims, currently have no treatment or cure.

SUMMARY OF THE DISCLOSURE

Among the various aspects of the present invention is the provision ofmethods for treatment of disease-induced ataxia and non-ataxicimbalance.

Briefly, therefore, the present invention is directed in one aspect to amethod of treating disease-induced ataxia or non-ataxic imbalance in ahuman, the method comprising administering to the human a compoundhaving nicotinic acetylcholine receptor activity.

Another aspect of the invention is directed to a method of treatingdisease-induced ataxia or non-ataxic imbalance in a human, the methodcomprising: determining a baseline measurement of ataxia or non-ataxicimbalance in the human and thereafter administering to the human acompound having nicotinic acetylcholine receptor activity; anddetermining a second measurement of ataxia or non-ataxic imbalance inthe human during or after administration of the compound, wherein animprovement in the second measurement relative to the baselinemeasurement indicates treatment of the ataxia or non-ataxic imbalance.

Another aspect of the invention is directed to a method of treatingdisease-induced ataxia or non-ataxic imbalance in a human, the methodcomprising: determining a baseline measurement of ataxia or non-ataxicimbalance in the human and thereafter administering to the human acompound having nicotinic acetylcholine receptor activity; anddetermining a second measurement of ataxia or non-ataxic imbalance inthe human at least one month after administration of the compound hasceased; wherein the second measurement is improved relative to thebaseline measurement.

Another aspect of the invention is directed to a method of treatingdisease-induced ataxia or non-ataxic imbalance in a human, the methodcomprising administering to the human a compound having nicotinicacetylcholine receptor activity, wherein a second measurement of ataxiaor non-ataxic imbalance measured after ceasing administration of thecompound is improved relative to a baseline measurement of ataxia ornon-ataxic imbalance measured prior to administration of the compound.

Another aspect of the invention is directed to use of a compound havingnicotinic acetylcholine receptor activity in the manufacture of amedicament for the treatment of disease-induced ataxia or non-ataxicimbalance.

Another aspect of the invention is directed to an (i) aryl-fusedazapolycyclic compound; (ii) pyridopyranoazepine; (iii) aryl-substitutedolefinic amine compound; (iv) benzylidene- or cinnamylidene-anabaseinecompound; (v) heterocyclic ether compound; (vi) 3-pyridyloxyalkylheterocyclic ether compound; (vii) N-substituted diazabicyclic compound;(viii) heterocyclic substituted amino azacycle compound; or (ix)indazole, benzothioazole, or benzoisothiazole compound for use in thetherapeutic treatment of disease-induced ataxia or non-ataxic imbalance.

Another aspect of the invention is directed to an aryl-fusedazapolycyclic compound for use in the therapeutic treatment ofdisease-induced ataxia or non-ataxic imbalance.

In each of these and other aspects, in one general embodiment thecompound may selected from the group consisting of ABT-089, ABT-894,alpha-bungarotoxin, anabaseine, bupropion, buspirone, BW284c51,cytisine, dianicline (SSR591813), dihydro-beta-erythoidine, DMXB, DMXB-A(GTS-21), diazoxon, donepezil, exelon, fluoxetine, galantamine,huperzine A, ispronicline (TC-1734/AZD-3480), lobeline, mecamylamine,MEM3454, MEM63908, methyllycaconitine, nefazodone, octanol/ethanol,OmIA, paroxetine, sertraline, tacrine, TC-2559, TC-5214((S)-(+)-mecamylamine), TC-5619, tebanicline (ABT-594), varenicline,venlafaxine, XY4083, and combinations thereof. In one generalembodiment, the compound is selected from the group consisting ofABT-089, ABT-894, bupropion, cytisine, dianicline (SSR591813), DMXB-A(GTS-21), ispronicline (TC-1734/AZD-3480), lobeline, mecamylamine,methyllycaconitine, TC-2559, TC-5214 ((S)-(+)-mecamylamine), tebanicline(ABT-594), varenicline, and combinations thereof. In another generalembodiment, the compound is selected from the group consisting ofdonepezil, exelon, fluoxetine, galantamine, huperzine A, MEM3454,MEM63908, tacrine, XY4083, and combinations thereof. In another generalembodiment of these and other aspects, the compound is, for example, asmoking cessation agent that operates through nicotinic acetylcholinereceptor activity; in one particular embodiment, for example, thecompound is varenicline.

Other objects and features will be in part apparent and in part pointedout hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a timeline of the clinical course of the patient of Example 1.

FIG. 2 is a T2 weighted image of the brain of the patient of Example 1.Note the white matter hyperintensities in the middle cerebellar peduncle(MCP) typical of FXTAS.

DETAILED DESCRIPTION

The present disclosure provides methods for the treatment of certaindisease-induced symptoms in a patient, typically a human. In particular,the symptoms are selected from ataxia and non-ataxic imbalance. Thedisclosure relates, in part, to the discovery that compounds havingnicotinic acetylcholine receptor activity (and pharmaceuticalcompositions including such compounds) may be used to treat ataxia andnon-ataxic imbalance stemming from a wide range of underlying diseases.Accordingly, a preferred embodiment of the present disclosure is the useof agents and compounds having nicotinic acetylcholine receptoractivity, such as, for example, varenicline, in methods for treatingataxia and non-ataxic imbalance. For example, one embodiment of thepresent disclosure is directed to method for treating disease-inducedataxia in a human, the method comprising administering to the human acompound having nicotinic acetylcholine receptor activity. Anotherembodiment of the present disclosure is directed to a method fortreating disease-induced non-ataxic imbalance in a human, the methodcomprising administering to the human a compound having nicotinicacetylcholine receptor activity. In certain of these and otherembodiments, the compound administered to the patient is varenicline.

Generally, the compounds having nicotinic acetylcholine receptoractivity may have agonistic, antagonistic, and/or modulatory activity.In certain embodiments, the compound having nicotinic acetylcholinereceptor activity is a nicotinic acetylcholine receptor agonist. In onepreferred embodiment, the compound is varenicline. These and othercompounds are used in methods for treating ataxia or non-ataxicimbalance resulting from a range of underlying diseases and medicalconditions, including diseases resulting from chronic or long-termexposure to toxins (such as drugs, alcohol, or other agents). Themethods comprise administering to the patient the nicotinicacetylcholine receptor-active compound.

As noted above, the methods disclosed herein involve administering to apatient exhibiting ataxic and/or non-ataxic imbalance symptoms,resulting from an underlying disease, a compound having nicotinicacetylcholine receptor activity. In certain embodiments, the patient isadministered a pharmaceutical composition comprising the compound; inone particular embodiment, the compound is varenicline. A patientreceiving such treatment may exhibit substantial improvement relative toa baseline score calculated or determined prior to treatment. Thetreatments disclosed herein are also capable of providing aneuroprotective or disease-modifying effect; that is, the treatmentinvolves affecting chemical or biochemical changes in the patient thatpersist even after treatment is stopped. Without being bound to anyparticular theory, it is believed that, over time, administration of thecompound stabilizes the cell membrane of a neuronal cell and/or helps inthe normalization of neuronal cell functions (e.g., the maintenance andrecovery of such functions).

The discovery that compounds having nicotinic acetylcholine receptoractivity can be used to treat ataxic and other symptoms from a widerange of diseases has clinical significance. Nicotinic acetylcholinereceptor-active compounds may be used to treat adverse symptoms ofataxia associated with, for example, Spinocerebellar ataxia, FragileX/Tremor ataxia syndrome, and Friedreich's ataxia, among a range ofothers.

One embodiment of the methods of the present disclosure, therefore,comprises administering to a human in need of such treatment a compoundhaving nicotinic acetylcholine receptor activity, typically in the formof a pharmaceutical composition comprising such compound. The compoundis generally administered in an effective amount; that is, a dose ofsufficient size to have a detectable therapeutic effect on the patient'sataxia and/or non-ataxic imbalance symptoms. The therapeutic effect maybe, for instance, any treatment that improves a patient's symptoms orotherwise reduces, alleviates, or minimizes such adverse conditions. Ingeneral, therefore, the treatment or treating of the symptoms discussedherein (i.e., ataxia or non-ataxic imbalance) refer to the improvement,amelioration, reduction, or minimization of these symptoms in anindividual. It will be appreciated by the person of ordinary skill inthe art that a treatment need not be completely effective in reducing oreliminating the symptom(s). Any reduction in the severity of symptoms ordelay in the progression of symptoms is desirable to a patient and thuscontemplated in the present disclosure. In this regard, it is noted thatthe methods described herein are not directed to treatment orprophylaxis of the underlying disease, but rather are directed toimproving, ameliorating, reducing, or minimizing the subjectiveindications that characterize the disease (i.e., the symptoms),including physical and physiological manifestations or reactions, and inparticular, ataxia and non-ataxic imbalance. The human patient may be,in various embodiments, an infant, child, adolescent, or adult.

Ataxia and Non-Ataxic Imbalance

As noted above, the present disclosure relates to the treatment ofataxia and/or non-ataxic imbalance. In general, a patient's ataxia ornon-ataxic imbalance symptoms may be manifested from a disease of anyetiology. The ataxia or non-ataxic imbalance may be the major or minorsymptom of a wide range of underlying diseases (including pathologicaldisorders or medical conditions). The patient's ataxia and non-ataxicimbalance is disease-induced; that is, it is caused by a disease, asdistinguished from drug-induced symptoms of ataxia and non-ataxicimbalance, e.g., resulting from the immediate exposure to drugs oralcohol or other toxins. Additionally or alternatively, underlyingdiseases manifesting in ataxia and non-ataxic imbalance may be unknown,thus the ataxia and non-ataxic imbalance may also result from idiopathiccases, including those due to anxiety or aging.

Ataxia, including both cerebellar ataxia and spinal ataxia (includingposterior spinal ataxia), generally involves the loss or failure ofmuscular coordination. Patients exhibiting ataxia may have difficultyregulating the force, range, direction, velocity, and rhythm of musclesinvolved in posture and balance. Ataxia of the trunk muscles, forexample, can result in increased postural sway, and an inability tomaintain the center of gravity over the base of support. Ataxia andprimary or secondary symptoms of ataxic gait and tremor of theextremities, may also lead to manifestations of speech disturbance,dysphagia, abnormal ventilation, and involuntary movements such asdystonia, and sometimes develops into vegetative symptoms or spasticparaplegia, as well as pyramidal or extrapyramidal symptoms, therebysubstantially interfering with the activities of daily life.

As noted above, ataxia may result from a wide range of underlyingdiseases and conditions in a patient, including cerebellar andneurodegenerative disorders and diseases resulting from chronic orlong-term exposure to toxins. Symptoms of ataxia may result from a widerange of diseases, disorders, and environmental factors, includinginfectious diseases, metabolic diseases, neurodegenerative diseases,genetic diseases, vascular diseases, neoplastic diseases, demyelinatingdiseases, neuromuscular diseases, and diseases resulting from long-termor chronic exposure to toxins (including drugs and alcohol), among avariety of others; in one embodiment, for example, the ataxia is theresult of a metabolic disease, a neurodegenerative disease, a vasculardisease, a neuromuscular diseases, or a disease resulting from long-termor chronic exposure to toxins. Diseases, disorders, syndromes, andconditions that may result in ataxic symptoms that may be treatedaccording to the methods described herein include, but are not limitedto, amyotrophic lateral sclerosis, benign paroxysmal positional vertigo,cerebellar ataxia type 1 (autosomal recessive), cerebellar ataxias(autosomal recessive), cerebellar ataxias (dominant pure), cerebellarcortical atrophy, cerebellar degeneration (subacute), cerebellardysfunction, cerebellar hypoplasia, cerebellar hypoplasia (endostealsclerosis), cerebellar hypoplasia (tapetoretinal degeneration),cerebelloparenchymal autosomal recessive disorder 3,cerebelloparenchymal disorder V, cerebellum agenesis (hydrocephaly),cerebral amyloid angiopathy (familial), cerebral palsy, demyelinatingdisorder, dorsal column conditions, dysautonomia, dysequilibriumsyndrome, dysethesis, endocrine diseases, diseases caused by chronicexposure to toxins (e.g., alcohol, drugs, antiepileptics, neuroleptics),Fragile X/Tremor ataxia syndrome, Friedreich's ataxia, frontal lobedysfunction, genetic diseases, granulomatous angiitis of the centralnervous system, Hallervorden-Spatz disease, Hereditary motor and sensoryneuropathy, hydrocephalus (e.g., low or normal pressure), hypotonia,congenital nystagmus, ataxia and abnormal auditory brainstem response,infantile onset spinocerebellar ataxia, Machado-Joseph disease,Meniere's disease, metabolic disorders, Miller Fisher Syndrome, Minamatadisease, multiple sclerosis, muscular dystrophy, Myoclonus-ataxia,neurodegenerative diseases, olivopontocerebellar atrophy, paraneoplasticdisorders, parkinsonism (atypical), peroneal muscular atrophy, phenylointoxicity, posterior column ataxia with retinitis pigmentosa, post-poliosyndrome, severe damage to the brain (caused by, e.g., head injury,brain surgery, multiple sclerosis or cerebral palsy, chronicalcohol/drug abuse, chronic exposure to toxins, viral infections, orbrain tumor), spastic hemiparesis, spastic paraplegia 23, spasticparaplegia glaucoma precocious puberty, SPG, spinocerebellar ataxia,spinocerebellar ataxia (amyotrophy—deafness), spinocerebellar ataxia(dysmorphism), spinocerebellar ataxia 11, spinocerebellar ataxia 17,spinocerebellar ataxia 20, spinocerebellar ataxia 25, spinocerebellarataxia 29, spinocerebellar ataxia 3, spinocerebellar ataxia (autosomalrecessive 1), spinocerebellar ataxia (autosomal recessive 3),spinocerebellar ataxia (autosomal recessive 4), spinocerebellar ataxia(autosomal recessive 5), spinocerebellar ataxia (autosomal recessive,with axonal neuropathy), spinocerebellar ataxia (Machado-Joseph typeII), spinocerebellar ataxia (X-linked, 2), spinocerebellar ataxia(X-linked, 3), spinocerebellar ataxia (X-linked, 4), spinocerebellardegenerescence (book type), stroke (e.g., acute or hemorrhagic),vertebral artery dissection, vertebral-basilar insufficiency, anddiseases caused by vitamin deficiencies, among a variety of others. Inone particular embodiment, the ataxia is the result of a diseaseselected from Spinocerebellar ataxia, Friedriech's ataxia, and fragileX/tremor ataxia syndrome. In another particular embodiment, the ataxiais the result of Spinocerebellar ataxia or fragile X/tremor ataxiasyndrome.

The present invention also relates to the treatment of non-ataxicimbalance. Non-ataxic imbalance generally refers to the loss of balanceand impaired coordination and vertigo that is related to the failure ofmuscular coordination. Like ataxia, symptoms of non-ataxic imbalance mayresult from a wide range of diseases, disorders, and environmentalfactors, including infectious diseases, metabolic diseases,neurodegenerative diseases, genetic diseases, vascular diseases,neoplastic diseases, demyelinating diseases, and neuromuscular diseases,among a variety of others; in one embodiment, for example, thenon-ataxic imbalance is the result of a metabolic disease, aneurodegenerative disease, a vascular disease, a neuromuscular diseases,or a disease resulting from long-term or chronic exposure to toxins.Particular diseases, disorders, syndromes, and stimuli that may resultin non-ataxic imbalance symptoms that may be treated according to themethods described herein include, but are not limited to, acousticneurinoma, agenesis of the corpus callosum, diseases caused by long-termdrug and alcohol abuse, Ataxia Telangiectasia, Angelman syndrome,general balance disorders (e.g., vertigo, falling sensation,unsteadiness, unbalance), brain cancer, cerebral palsy, ChiariMalformation, classic childhood ALD, corticobasal degeneration, herpeszoster oticus, HIV/AIDS, hydrocephalus, multiple sclerosis, musculardystrophy, olivopontocerebellar atrophy, Parkinson's Disease, atypicalparkinsonism, Rett's Syndrome, Shy-Drager Syndrome, stroke, vertigo, VonHippel-Lindau Disease, Wallenberg's Syndrome, and Wilson's Disease,among a variety of others. In one particular embodiment, the non-ataxicimbalance is the result of a disease selected from Spinocerebellarataxia, Friedriech's ataxia, and fragile X/tremor ataxia syndrome. Inanother particular embodiment, the non-ataxic imbalance is the result ofSpinocerebellar ataxia or fragile X/tremor ataxia syndrome.

Compounds Having Nicotinic Acetylcholine Receptor Activity

Compounds for treating ataxia or non-ataxic imbalance symptoms accordingto the methods described herein have nicotinic acetylcholine receptoractivity. As noted above, this activity may be agonistic, antagonistic,or modulatory. The compound(s) may have an effect on either the neuronaltype nicotinic acetylcholine receptors, the muscle type nicotinicacetylcholine receptor, or both. For example, the compound may becapable of acting on the α1, β1, δ, γ, and ε receptor subunits, andcombinations thereof. By way of another example, the compound may becapable of acting on the various homomeric or heteromeric combinationsof seventeen different nicotinic receptor subunits: α2 through α10 andβ2 through β4 (e.g., the neuronal subtypes: (α4)₃(β2)₂, (α4)₂(β2)₃, and(α7)₅). Generally speaking, this includes, for instance, compoundshaving activity on Neuronal Type I receptor subunits (e.g., α9, α10),Neuronal Type II receptor subunits (e.g., α7, α8), Neuronal Type III(1)receptor subunits (e.g., α2, α3, α4, and α6), Neuronal Type III(2)receptor subunits (e.g., (β2, β4), Neuronal Type III(3) receptorsubunits (e.g., (β3, β5), Muscle Type IV receptor subunits (e.g., α1,β1, δ, γ, and ε), and combinations thereof.

For example, the compound may be an agonist or partial agonist(including selective agonist or selective partial agonist) of the α4β2receptor (e.g., ABT-089, ABT-894, cytosine, dianicline (SSR591813),TC-1734, TC-2559, and varenicline, among others). In additional oralternative examples, the compound may be an antagonist of the α4β2receptor (e.g., anabaseine, DMXB-A, lobeline, mecamylamine,methyllycaconitine, and TC-5214, among others). In another example, thecompound may be an antagonist (including non-competitive antagonists) ofthe α3β2 receptor (e.g., alpha-bungarotoxin, bupropion, fluoxetine,lobeline, and mecamylamine, among others). By way of another example,the compound may be an agonist (including selective agonists) of the α7receptor (e.g., anabaseine, DMXB-A, galantamine, MEM3454, MEM63908,TC-5214, and varenicline, among others). In another example, thecompound may be an antagonist of the α7 receptor (e.g.,alpha-bungarotoxin, dihydro-beta-erythroidine, mecamylamine, paroxetine,sertraline, and venlafaxine, among others). In another example, thecompound may be an antagonist of the α3β4 receptor (e.g.,alpha-bungarotoxin, bupropion, fluoxetine, lobeline, and mecamylamine,among others). By way of another example, the compound may be anantagonist of the α3β4 receptor (e.g., fluoxetine, nefazodone,paroxetine, sertraline, and venlafaxine, among others). By way of yetanother example, the compound may have activity (e.g., agonistic,antagonistic, or other activity) on the α3β2, α6, β2, (α1)2β1δε and(α1)2β1δγ, α3, and/or α6β2 receptors (e.g., varenicline, cytosine,alpha-bungarotoxin, ABT-594, and OmIA, among others).

In some instances, the active agent having nicotinic acetylcholinereceptor activity is a known compound with proven clinical efficacy, forexample, in smoking cessation. In certain embodiments, the compound isselected from the group consisting of (i) an aryl-fused azapolycycliccompound; (ii) a pyridopyranoazepine; (iii) an aryl-substituted olefinicamine compound; (iv) a benzylidene- or cinnamylidene-anabaseinecompound; (v) a heterocyclic ether compound; (vi) 3-pyridyloxyalkylheterocyclic ether compound; (vii) an N-substituted diazabicycliccompound; (viii) a heterocyclic substituted amino azacycle compound; and(ix) an indazole, benzothioazole, or benzoisothiazole compound. In oneembodiment, the compound is selected from the group consisting ofABT-089, ABT-894, alpha-bungarotoxin, anabaseine, bupropion, buspirone,BW284c51, cytisine, dianicline (SSR591813), dihydro-beta-erythoidine,DMXB, DMXB-A (GTS-21), diazoxon, donepezil, exelon, fluoxetine,galantamine, huperzine A, ispronicline (TC-1734/AZD-3480), lobeline,mecamylamine, MEM3454, MEM63908, methyllycaconitine, nefazodone,octanol/ethanol, OmIA, paroxetine, sertraline, tacrine, TC-2559, TC-5214((S)-(+)-mecamylamine), TC-5619, tebanicline (ABT-594), varenicline,venlafaxine, XY4083, and combinations thereof. In particular embodiment,the compound is selected from the group consisting of ABT-089, ABT-894,bupropion, cytisine, dianicline (SSR591813), DMXB-A (GTS-21),ispronicline (TC-1734/AZD-3480), lobeline, mecamylamine,methyllycaconitine, TC-2559, TC-5214 ((S)-(+)-mecamylamine), tebanicline(ABT-594), varenicline, and combinations thereof. In another particularembodiment, the compound is selected from the group consisting ofdonepezil, exelon, fluoxetine, galantamine, huperzine A, MEM3454,MEM63908, tacrine, XY4083, and combinations thereof. In a preferredembodiment, the compound is selected from the group consisting ofvarenicline, dianicline, ispronicline, and combinations thereof; morepreferably in this embodiment, the compound is varenicline.

In one particular embodiment, the compound is an aryl-fusedazapolycyclic compound. According to this embodiment, for example, thecompound administered to the patient may have the formula (i):

wherein R₁ is hydrogen, (C₁-C₆)alkyl, unconjugated (C₃-C₆)alkenyl,benzyl, XC(═O)R₁₃ or —CH₂CH₂—O—(C₁-C₄)alkyl;

R₂ and R₃ are selected, independently, from hydrogen, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, hydroxy, nitro, amino, halo, cyano, —SO_(q)(C₁-C₆)alkylwherein q is zero, one or two, (C₁-C₆)alkylamino-,[(C₁-C₆)alkyl]₂amino-, —CO₂R₄, —CONR₅R₆, —SO₂NR₇R₈, —C(═O)R₁₃,—XC(═O)R₁₃, aryl-(C₀-C₃)alkyl- or aryl-(C₀-C₃)alkyl-O—, wherein saidaryl is selected from phenyl and naphthyl, heteroaryl-(C₀-C₃)alkyl- orheteroaryl-(C₀-C₃)alkyl-O—, wherein said heteroaryl is selected fromfive to seven membered aromatic rings containing from one to fourheteroatoms selected from oxygen, nitrogen and sulfur, andX₂(C₀-C₆)alkoxy-(C₀-C₆)alkyl-, wherein X₂ is absent or X₂ is(C₁-C₆)alkylamino- or [(C₁-C₆)alkyl]₂amino-, and wherein the(C₀-C₆)alkoxy-(C₀-C₆)alkyl- moiety of said X₂(C₀-C₆)alkoxy-(C₀-C₆)alkyl-contains at least one carbon atom, and wherein from one to three of thecarbon atoms of said (C₀-C₆)alkoxy-(C₀-C₆)alkyl- moiety may optionallybe replaced by an oxygen, nitrogen or sulfur atom, with the proviso thatany two such heteroatoms must be separated by at least two carbon atoms,and wherein any of the alkyl moieties of said(C₀-C₆)alkoxy-(C₀-C₆)alkyl- may be optionally substituted with from twoto seven fluonne atoms, and wherein one of the carbon atoms of each ofthe alkyl moieties of said aryl-(C₀-C₃)alkyl- and saidheteroaryl-(C₀-C₃)alkyl- may optionally be replaced by an oxygen,nitrogen or sulfur atom, and wherein each of the foregoing aryl andheteroaryl groups may optionally be substituted with one or moresubstituents, preferably from zero to two substituents, independentlyselected from (C₁-C₆)alkyl optionally substituted with from one to sevenfluonne atoms, (C₁-C₆)alkoxy optionally substituted with from two toseven fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo),(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy, nitro, cyano, amino, (C₁-C₆)—,[(C₁-C₆)alkyl]₂amino-, —CO₂R₄, —CONR₅R₆, —SO₂NR₇R₈, —C(═O)R₁₃ and—XC(═O)R₁₃; or R₂ and R₃, together with the carbons to which they areattached, form a four to seven membered monocyclic, or a ten to fourteenmembered bicyclic, carbocyclic ring that can be saturated orunsaturated, wherein from one to three of the nonfused carbon atoms ofsaid monocyclic rings, and from one to five of the carbon atoms of saidbicyclic rings that are not part of the benzo ring shown in formula (i),may optionally and independently be replaced by a nitrogen, oxygen orsulfur, and wherein said monocyclic and bicyclic rings may optionally besubstituted with one or more substituents, preferably from zero to twosubstituents for the monocyclic rings and from zero to threesubstituents for the bicyclic rings, that are selected, independently,from (C₀-C₆)alkoxy-(C₀-C₆)alkyl-, wherein the total number of carbonatoms does not exceed six and wherein any of the alkyl moieties mayoptionally be substituted with from one to seven fluorine atoms; nitro,oxo, cyano, halo, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, hydroxy, amino,(C₁-C₆)alkylamino-, [(C₁-C₆)alkyl]₂amino-, —CO₂R₄, —CONR₅R₆, —SO₂NR₇R₈,—C(═O)R₁₃, and —XC(═O)R₁₃;

each R₄, R₅, R₆, R₇, R₈ and R₁₃ is selected, independently, fromhydrogen and (C₁-C₆) alkyl, or R₅ and R₆, or R₇ and R₈ together with thenitrogen to which they are attached, form a pyrrolidine, piperidine,morpholine, azetidine, piperazine, —N—(C₁-C₆)alkylpiperazine orthiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur isreplaced with a sulfoxide or sulfone; and each X is, independently,(C₁-C₆)alkylene: with the proviso that: (a) at least one of R₁, R₂ andR₃ must be the other than hydrogen, and (b) when R₂ and R₃ are hydrogen,R₁ cannot be methyl or hydrogen; and the pharmaceutically acceptablesalts of such compounds.

In a particular embodiment, R₁, R₂, and R₃ are each hydrogen; morepreferably in this embodiment, the compound has the formula:

This compound 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino (2,3-h)(3)benzazepine (also known as varenicline or Chantix®) is approved as amedication for the treatment nicotine dependence. Compoundscorresponding to formula (i) and varenicline are described in furtherdetail in International Publication No. WO2001/062736; U.S. Pat. No.6,410,550; U.S. Pat. No. 6,605,610; U.S. Pat. No. 6,890,927; and U.S.Pat. No. 7,265,119 (each of which is hereby incorporated by referenceherein in its entirety). In a particular embodiment, the compoundadministered to the patient is varenicline.

In another particular embodiment, the compound is a pyridopyranoazepine.According to this embodiment, for example, the compound administered tothe patient may have the formula (ii):

wherein R₁ is a hydrogen atom, a (C₁-C₄)alkyl group, aphenyl(C₁-C₄)alkyl group, a phenylhydroxy(C₁-C₄)alkyl group, afuranyl(C₁-C₄)alkyl group, or a furanyl-hydroxy(C₁-C₄)alkyl group, R₂ iseither a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxyl,nitro, acetyl, (C₁-C₆)alkyl or (C₁-C₆)alkoxy group or a group of generalformula NR₄R₅ in which R₄ is a hydrogen atom or a (C₁-C₄)alkyl or(C₁-C₄)alkanoyl group and R₅ is a hydrogen atom or a (C₁-C₄)alkyl group,or else R₄ and R₅ form, with the nitrogen atom which carries them, aC₄-C₇ ring, or a phenyl or naphthyl group optionally substituted by ahalogen atom or a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl,nitro, acetyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy or methylenedioxy grouplinked in the 2 and 3 positions of the phenyl ring, and R₃ is a hydrogenor halogen atom or a (C₁-C₄)alkyl group.

The compounds of general formula (ii) can exist in the state of bases orof addition salts to acids. In addition, the atoms in positions 5a and10a being asymmetric, a compound can exist in the form of pure geometricand optical isomers or of mixtures of the latter. In a particularembodiment, R₁, R₂, and R₃ are each hydrogen; more preferably in thisembodiment, the compound has the formula:

This compound (5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine (also known asSSR-591,813 or dianicline) is presently in clinical trials as amedication for the treatment nicotine dependence. Compoundscorresponding to formula (ii) and dianicline (SSR591813) are describedin further detail in U.S. Pat. No. 6,538,003 (hereby incorporated byreference herein in its entirety).

In another particular embodiment, the compound is an aryl-substitutedolefinic amine compound. According to this embodiment, for example, thecompound administered to the patient may have the formula (iii):

where each of X and X′ are individually nitrogen or carbon bonded to asubstituent species characterized as having a sigma m value greater than0, often greater than 0.1, and generally greater than 0.2, and evengreater than 0.3; less than 0 and generally less than −0.1; or 0; asdetermined in accordance with Hansch et al., Chem. Rev. 91:165 (1991); mis an integer and n is an integer such that the sum of m plus n is 1, 2,3, 4, 5, 6, 7, or 8, preferably is 1, 2, or 3, and most preferably is 2or 3; the wavy line in the structure indicates that the compound canhave the cis (Z) or trans (E) form; E^(I), E^(II), E^(III), E^(IV),E^(V) and E^(VI) individually represent hydrogen or lower alkyl (e.g.,straight chain or branched alkyl including C₁-C₈, preferably C₁-C₅, suchas methyl, ethyl, or isopropyl) or halo substituted lower alkyl (e.g.,straight chain or branched alkyl including C₁-C₈, preferably C₁-C₅, suchas trifluoromethyl or trichloromethyl), and at least one of E^(I),E^(II), E^(III), E^(IV), E^(V) and E^(VI) is non-hydrogen and theremaining E^(I), E^(II), E^(III), E^(IV), E^(V) and E^(VI) are hydrogen;and Z′ and Z″ individually represent hydrogen or lower alkyl (e.g.,straight chain or branched alkyl including C₁-C₈ preferably C₁-C₅, suchas methyl, ethyl, or isopropyl), and preferably at least one of Z and Z″is hydrogen, and most preferably Z′ is hydrogen and Z″ is methyl;alternatively Z′ is hydrogen and Z″ represents a ring structure(cycloalkyl or aromatic), such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, quinuclidinyl, pyridyl, quinolinyl,pyrimidinyl, phenyl, benzyl (where any of the foregoing can be suitablysubstituted with at least one substituent group, such as alkyl, halo, oramino substituents); alternatively Z′, Z″, and the associated nitrogenatom can form a ring structure such as aziridinyl, azetidinyl,pyrollidinyl, piperidinyl, quinuclidinyl, piperazinyl, or morpholinyl.

Representative compounds having the generic structure (iii) include(4E)-N-methyl-5-(3-pyridyl)-4-pen-ten-2-amine,(4E)-N-methyl-5-(5-pyrimidinyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(6-amino-5-methyl-3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(2R)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-bromo-3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-ethoxy-3-pyridyl)-4-penten-2-amine,(2S)-(4E)-N-methyl-5-(3-pyridyl)-4-penten-2-amine,(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine and(2S)-(4E)-N-methyl-5-(5-isopropoxy-3-pyridyl)-4-penten-2-amine (alsoknown as ispronicline, TC-1734, or AZD-3480). Compounds corresponding toformula (iii) are described in further detail in InternationalPublication WO 99/65876 and WO 00/75710; U.S. Patent ApplicationPublication 2002/0052497; U.S. Pat. No. 6,979,695; and U.S. Pat. No.7,045,538 (each of which is hereby incorporated by reference herein inits entirety).

In another particular embodiment, the compound is a benzylidene- orcinnamylidene-anabaseine compound. According to this embodiment, forexample, the compound administered to the patient may have the formula(iv):

or a salt thereof, wherein R₁, R₆ and R₇ are hydrogen or C₁-C₄ alkyl;and R₂ is ═CHCH═CHX, wherein X is

wherein R₃, R₄, and R₅ are selected from the group consisting ofhydrogen, C₁-C₄ alkyl optionally substituted with N,N-dialkylaminohaving 1 to 4 carbon atoms in each of the alkyls, C₁-C₆ alkoxyoptionally substituted with N,N-dialkylamino having 1 to 4 carbons ineach of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy(such as acetoxy), amino, amido having 1 to 4 carbons in the acyl (suchas acetylamino), cyano, N,N-dialkylamino having 1 to 4 carbons in eachof the alkyls, halo, hydroxyl, and nitro.

Representative cinnamylidene-anabaseines having the generic structure(iv) include, but are not limited to, 3-(4-acetylaminocinnamylidene)anabaseine, 3-(4-hydroxycinnamylidene)anabaseine,3-(4-methoxycinnamylidene)anabaseine,3-(4-hydroxy-2-methoxycinnamylidene)anabaseine,3-(2,4-dimethoxycinnamylidene)anabaseine, and3-(4-acetoxycinnamylidene)anabaseine. Representativebenzylidene-anabaseines having the generic structure (iv) include, butare not limited to, 3-(2,4-dimethoxybenzylidene)anabaseine (also knownas DMXB-A and GTS-21), 3-(4-hydroxybenzylidene)anabaseine,3-(4-methoxybenzylidene)anabaseine, 3-(4-aminobenzylidene) anabaseine,3-(4-hydroxy-2-methoxybenzylidene)anabaseine,3-(2-hydroxy-4-methoxybenzylidene)anabaseine,3-(4-isopropoxybenzylidene)anabaseine, and(7′-methyl-3-(2,4-dimethoxybenzylidene)). Compounds corresponding toformula (iv) are described in further detail in InternationalPublication WO 99/10338 and WO 2006/133303; U.S. Pat. No. 5,741,802; andU.S. Pat. No. 5,977,144 (each of which is hereby incorporated byreference herein in its entirety).

In another particular embodiment, the compound is a heterocyclic ethercompound. According to this embodiment, for example, the compoundadministered to the patient may have the formula (v):

wherein the asterisk indicates a chiral center; n is 1, 2, or 3; y is 1or 2; R₁ is H, allyl or C₁-C₆-alkyl; R₂ is H, F, Cl, or C₁-C₃-alkyl; andR₃ is independently selected from H, F, Cl, Br or C₁-C₆-alkyl; with theprovisos that (a) when R₂ is C₁-C₃-alkyl, then R₁ is H, and (b) when yis 2, then R₂ is hydrogen.

Representative heterocyclic ethers having the generic structure (v)include, but are not limited to, 3-(2-(S)-azetidinylmethoxy)pyridine;3-((1-methyl-2-S)-azetidinyl)methoxy)pyridine;2-methyl-3-(2-(S)-azetidinylmethoxy)pyridine (also known as ABT-089);5-chloro-3-(2-(S)-azetidinylmethoxy)pyridine;5-([(2R)-azetidin-2-yl]methoxy)-2-chloropyridine (also known astebanicline or ABT-594); 6-methyl-3-(2-(S)-azetidinylmethoxy)pyridine;3-(2-(S)-azetidinylmethoxy)chloropyridine;3-(2-(R)-azetidinylmethoxy)pyridine;3-((1-methyl-2-(R)-azetidinyl)methoxy)pyridine;3-(2-(S)-azetidinylmethoxy)-5-bromopyridine;3-((1-methyl-2-(S)-azetidinyl)methoxy)-5-bromopyridine; and5,6-dichloro-3-(2-(S)-azetidinylmethoxy)pyridine;3-(2-(R)-pyrrolidinylmethoxy)pyridine;3-(2-(S)-pyrrolidinylmethoxy)pyridine;5-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine;2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine;6-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine;5-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine;6-methyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine;3-(2-(S)-pyrrolidinylmethoxy)-6-chloropyridine;5-bromo-3-(2-(S)-pyrrolidinylmethoxy)pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;5-chloro-3-(1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;6-methyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;5-bromo-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;6-chloro3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;5-n-butyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;5-n-propyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;5-methyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; and5-ethyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; or apharmaceutically-acceptable salt or prodrug thereof. Compoundscorresponding to formula (v) are described in further detail inInternational Publication WO 99/32480; U.S. Pat. No. 5,914,328; and U.S.Pat. No. 5,948,793 (each of which is hereby incorporated by referenceherein in its entirety).

In another particular embodiment, the compound is a 3-pyridyloxyalkylheterocyclic ether compound. According to this embodiment, for example,the compound administered to the patient may have the formula (vi):

wherein the asterisk indicates a chiral center; n is an integer selectedfrom 1, 2, or 3; X is oxygen or sulfur; R₁ is H, allyl or C₁-C₆-alkyl;R₂ is hydrogen, or when n=2, is a single substituent selected from thegroup consisting of —CH₂OH, —CH₂F, —CH₂CN, —CH₂OCH₃, —Br, —Cl, —F, —OH,—CH, —(C₁-C₃ alkoxyl), —OCOCH₃, and O-methanesulfonyl, with the provisothat when R₂ is substituted at the 3-position or the 5-position of thepyrrolidinyl ring, it is a C₁-C₃ group; A is selected from the groupconsisting of:

where R₃ is H or C₁-C₆ alkyl; y is 1, 2, or 3 with the provisos that a)when y=1, R₄ is selected from the group consisting of (i) a singlesubstituent at the 2-position of the pyridine ring selected fromchlorine and fluorine, and (ii) a single substituent substituted at the5- or 6-position of the pyridine ring selected from the group consistingof —CN, —CF₃, —NO₂, —CH₂OH, —CH₂CN, —NH₂, —NH—CHO, —NHCO(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)-CO(C₁-C₃ alkyl), —NH—(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—COOH, —COO(C₁-C₃ alkyl), —CONH₂, —CONH(C₁-C₃ alkyl), —CONHbenzyl, and—OCO(C₁-C₃-alkyl); b) when y=2, R⁴ is substituted at the 2,5-, 2,6- or5,6-positions of the pyridine ring wherein the 2-position substituent isselected from the group consisting of —Br, —Cl, —F, —OH, —(C₁-C₄ alkyl)and —(C₁-C₃ alkoxy) and the substituents at the 5- or 6-positions of thepyridine ring are selected from the group consisting of —Br, —Cl, —F,—OH, —(C₁-C₄ alkyl), —CN, —CF₃, —NO₂, —CH₂OH, —CH₂CN, alkoxy), —NH₂,—NH—CHO, —NHCO(C₁-C₃ alkyl), —N(C₃-C₃ alkyl)CO(C₁-C₃ alkyl), —NH—(C₁-C₃alkyl), —N(C₁-C₃ alkyl)₂, —COOH, —COO(C₁-C₃ alkyl), —CONH₂, —CONH—(C₁-C₃alkyl), —CONHbenzyl, and —OCO(C₁-C₃ alkyl); and c) when y=3, R₄ is asubstituent at the 2-position of the pyridine ring selected from thegroup consisting of —Br, —Cl, —F, —OH, —C₁-C₄ alkyl, and —C₁-C₃ alkoxy;and second and third substituents at the 5- and 6-position of thepyridine ring are independently selected from the group consisting of—Br, —Cl, —F, —OH, —C₁-C₄ alkyl, —CN, —CF₃, —NO₂, —CH₂OH, —CH₂CN,—(C₁-C₃ alkoxy), —NH₂, —NH—CHO, —NHCO(C₁-C₃ alkyl), —N(C₁-C₃alkyl)CO(C₁-C₃ alkyl), —NH—(C₁-C₃alkyl), —N(C₁-C₃-alkyl)₂, —COOH,—COO(C₁-C₃-alkyl), —CONH₂, —CONH(C₃-C₃ alkyl), —CONHbenzyl, and—OCO(C₁-C₃ alkyl).

Compounds corresponding to formula (vi) are described in further detailin International Publication WO 96/040682 (hereby incorporated byreference herein in its entirety).

In another particular embodiment, the compound is a N-substituteddiazabicyclic compound. According to this embodiment, for example, thecompound administered to the patient may have the formula (vii):

or pharmaceutically acceptable salts and prodrugs thereof, wherein A isselected from the group consisting of a covalent bond, CH₂, CH₂CH₂, andCH₂CH₂CH₂; B is selected from the group consisting of CH₂ and CH₂CH₂,provided that when A is CH₂CH₂CH₂, then B is CH₂; Y is selected from thegroup consisting of a covalent bond, CH₂, and CH₂CH₂; Z is selected fromthe group consisting of a covalent bond, CH₂, and CH₂CH₂, provided thatwhen Y is CH₂CH₂, then Z is a covalent bond and further provided thatwhen Z is CH₂CH₂, then Y is a covalent bond;

R₁ is selected from the group consisting of:

R₃ is selected from the group consisting of hydrogen, alkyl, andhalogen;

R₄ is selected from the group consisting of hydrogen, alkoxy, alkyl,amino, halogen, and nitro;

R₅ is selected from the group consisting of hydrogen, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminoalkyl,aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, carboxy, carboxyalkyl,cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, 5-tetrazolyl,—NR₆S(O)₂R₇, —C(NR₆)NR₇R₈, —CH₂C(NR₆)NR₇R₈, —C(NOR₆)R₇, —C(NCN)R₆,—C(NNR₆R₇)R₈, —S(O)₂OR₆, and —S(O)₂R₆;

R₆, R₇, and R₈ are independently selected from the group consisting ofhydrogen and alkyl;

and R₉ is selected from the group consisting of hydrogen,alkoxycarbonyl, alkyl, amino, aminoalkyl, aminocarbonylalkyl,benzyloxycarbonyl, cyanoalkyl, dihydro-3-pyridinylcarbonyl, hydroxy,hydroxyalkyl, and phenoxycarbonyl.

Representative heterocyclic ethers having the generic structure (vii)include, but are not limited to,(1R,5R)-6-(6-chloro-3-pyridinyl)-2,6-diazabicyclo[3.2.0]heptane;(1R,5R)-6-(3-pyridinyl)-2,6-diazabicyclo[3.2.0]heptane;(cis)-6-(3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(cis)-6-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1R,5S)-6-(3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1R,5S)-6-(5-bromo-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1S,5R)-6-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1S,5R)-6-(3-pyridinyl)-3,6diazabicyclo[3.2.0]heptane;(1R,5S)-6-(6-chloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1S,5R)-6-(5-ethynyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1S,5R)-6-(5-vinyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;5-[(1S,5R)-3,6-diazabicyclo[3.2.0]hept-6-yl]nicotinonitrile;(1S,5R)-6-(5-bromo-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1S,5R)-6-(6-bromo-5-vinyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;2-bromo-5-[(1R,5S)-3,6-diazabicyclo[3.2.0]hept-6-yl]nicotinonitrile;(1R,5S)-6-(5-ethynyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;5-[(1R,5S)-3,6-diazabicyclo[3.2.0]hept-6-yl]nicotinonitrile;(cis)-8-(3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(cis)-8-(6-chloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane; (1S,6R)(cis)-8-(6-chloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane; (−)(cis)-8-(6-chloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;5-[(1R,6S)-3,8-diazabicyclo[4.2.0]oct-8-yl]nicotinonitrile;(1S,6R)-5-[3,8-diazabicyclo[4.2.0]oct-8-yl]nicotinonitrile;(1R,5S)-6-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1S,5R)-6-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(cis)-6-(5,6-dichloro-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(cis)-8-(5-methoxy-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(1R,5S)-6-(5-methoxy-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1S,5R)-6-(5-methoxy-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(cis)-6-(6-bromo-5-methoxy-3-pyridinyl)-3,6diazabicyclo[3.2.0]heptane;(1R,5S)-6-(6-chloro-5-methyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1S,5R)-6-(6-chloro-5-methyl-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1S,6R) (cis)-8-(5-methoxy-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(1R,6S)-8-(5-methoxy-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(cis)-8-(6-chloro-5-methyl-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(1S,6R)-8-(6-chloro-5-methyl-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(1R,6S)-8-(6-chloro-5-methyl-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(1S,6R)-8-(3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(1R,6S)-8(3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(cis)-8-(5,6-dichloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane(1S,6R)-8-(5,6-dichloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(1R,6S)-8-(5,6-dichloro-3-pyridinyl)-3,8-diazabicyclo[4.2.0]octane;(cis)-6-(6-bromo-5-methoxy-3-pyridinyl)-3,6-diazabicyco[3.2.0]heptane;(1R,5S)-6-(6-bromo-5-methoxy-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(1S,5R)-6-(6-bromo-5-methoxy-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane;(cis)-6-(5-azido-3-pyridinyl)-3,6-diazabicylo[3.2.0]heptane;(1R,5S)-6-(5-azido-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane; and(1R,5S)-6-(5-azido-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane.Compounds corresponding to formula (vii) are described in further detailin International Publication WO 2004/0186107; and U.S. Pat. No.6,809,105 (each of which is hereby incorporated by reference herein inits entirety).

In another particular embodiment, the compound is a heterocyclicsubstituted amino azacycle compound. According to this embodiment, forexample, the compound administered to the patient may have the formula(viii):Z—R₃  (viii)

wherein Z is selected from the group consisting of:

R₁ and R₂ are independently selected from the group consisting ofhydrogen and alkyl; A and B are independently absent or independentlyselected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl,alkyl, alkynyl, carboxy, haloalkyl, halogen, hydroxyl, and hydroxyalkyl;R₃ is selected from the group consisting of:

R₄ is selected from the group consisting of hydrogen, alkyl, andhalogen; R₅ is selected from the group consisting of hydrogen, alkyl,halogen, nitro, and —NR₁₀R₁₁, wherein R₁₀ and R₁₁ are independentlyselected from the group consisting of hydrogen and lower alkyl; R₆ isselected from the group consisting of hydrogen, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkynyl, amino, aminoalkyl,aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, carboxy, carboxyalkyl,cyano, cyanoalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, halogen,hydroxyl, hydroxyalkyl, mercapto, mercaptoalkyl, nitro, 5-tetrazolyl,—NR₇SO₂R₈, —C(NR₇)NR₈R₉, —CH₂C(NR₇)NR₈R₉, —C(NOR₇)R₈, —C(NCN)R₇,—C(NNR₇R₈)R₉, —S(O)₂OR₇, and —S(O)₂R₇; and R₇, R₈, and R₉ areindependently selected from the group consisting of hydrogen and alkyl;provided that when R₃ is pyridazine then R₁ is alkyl.

Representative compounds of formula (viii) include, but are not limitedto: N-[(3S)-1-(6-chloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;(3S)-1-(6-chloro-3-pyridinyl)pyrrolidinylamine;N-[(3S)-1-(6-chloro-3-pyridinyl)pyrrolidinyl]-N,N-dimethylamine;(3R)-1-(6-chloro-3-pyridinyl)pyrrolidinylamine;N-[(3R)-1-(6-chloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;N-[(3R)-1-(6-chloro-3-pyridinyl)pyrrolidinyl]-N,N-dimethylamine;1-(6-chloro-3-pyridinyl)-3-pyrrolidinylamine;(3S)-1-(3-pyridinyl)pyrrolidinylamine;N-methyl-N-[(3S)-1-(3-pyridinyl)pyrrolidinyl]amine;1-(3-pyridinyl)-3-pyrrolidinylamine;(3R)-1-[5-(trifluoromethyl)-3-pyridinyl]pyrrolidinylamine;N-methyl-N-{(3R) 1-[5-(trifluoromethyl)-3-pyridinyl]pyrrolidinyl}amine;(3S)-1-[5-(trifluoromethyl)-3-pyridinyl]pyrrolidinylamine;N-methyl-N-{(3S)-1-[5-(tri fluoromethyl)-3-pyridinyl]pyrrolidinyl}amine;(3R)-1-(6-chloro-5-chloro-5-methyl-3-pyridinyl)pyrrolidinyl amine;N-[(3R)-1-(6-chloro-5-methyl-3-pyridinyl)pyrrolidinyl]-N-methylamine;(3S)-1-(6-chloro-5-methyl-3-pyridinyl)pyrrolidinylamine;N-[(3S)-1-(6-chloro-5-methyl-3-pyridinyl)pyrrolidinyl]-N-methylamine;(3S)-1-(5,6-dichloro-3-pyridinyl)pyrrolidinylamine;N-[(3S)-1-(5,6-dichloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;(3R)-1-(5,6-dichloro-3-pyridinyl)pyrrolidinylamine;N-[(3R)-1-(5,6-dichloro-3-pyridinyl)pyrrolidinyl]-N-methylamine;(3S)-1-(6-chloro-5-methoxy-3-pyridinyl)pyrrolidinylamine;N-[(3S)-1-(6-chloro-5-methoxy-3-pyridinyl)pyrrolidinyl]-N-methylamine;(3S)-1-(6-fluoro-5-methyl-3-pyridinyl)pyrrolidinylamine;N-[(3S)-1-(6-fluoro-5-methyl-3-pyridinyl)pyrrolidinylamine;N-[(3S)-1-(6-fluoro-5-methyl-3-pyridinyl)pyrrolidinyl]-N-methylamine;(3R)-1-(6-fluoro-5-methyl-3-pyridinyl)pyrrolidinylamine;N-[(3R)-1-(6-fluoro-5-methyl-3-pyridinyl)pyrrolidinyl]-N-methylamine;(3S)-1-(5-nitro-3-pyridinyl)pyrrolidinylamine;N-methyl-N-[(3S)-1-(5-nitro-3-pyridinyl)pyrrolidinyl]amine;(3R)-1-(5-nitro-3-pyridinyl)pyrrolidinylamine;N-methyl-N-[(3R)-1-(5-nitro-3-pyridinyl)pyrrolidinyl]amine; and(2S,3R)-2-(chloromethyl) 1-(3-pyridinyl)pyrrolidinylamine. Compoundscorresponding to formula (viii) are described in further detail inInternational Publication WO 00/71534; and U.S. Pat. No. 6,833,370 (eachof which is hereby incorporated by reference herein in its entirety).

In another particular embodiment, the compound is an indazole,benzothioazole, or benzoisothiazole. According to this embodiment, forexample, the compound administered to the patient may have the formulae(ix)(a), (ix)(b), (ix)(c), or (ix)(d):

wherein A is:

wherein the slanted line through the fused rings represent the bond ofattachment from the fused chemical moiety to the remainder of thecompound; X is O or S; R₁ is H, F, Cl, Br, I, OH, CN, nitro, NH₂, alkylhaving 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms(e.g., CF₃), cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkylhaving 4 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms (e.g.,OCH₃), cycloalkoxy having 3 to 7 carbon atoms, cycloalkylalkoxy having 4to 7 carbon atoms, alkylthio having 1 to 4 carbon atoms (e.g., SCH₃),fluorinated alkoxy having 1 to 4 carbon atoms (e.g., OCF₃, OCHF₂),hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4carbon atoms, monoalkylamino having 1 to 4 carbon atoms, dialkylaminowherein each alkyl group independently has 1 to 4 carbon atoms, Ar orHet; R₂ is H, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms; R₃ is H, F,Cl, Br, I, OH, CN, nitro, NH₂, alkyl having 1 to 4 carbon atoms,fluorinated alkyl having 1 to 4 carbon atoms (e.g., CF₃), cycloalkylhaving 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms,alkoxy having 1 to 4 carbon atoms (e.g., OCH₃), cycloalkoxy having 3 to7 carbon atoms, cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthiohaving 1 to 4 carbon atoms (e.g., SCH₃), fluorinated alkoxy having 1 to4 carbon atoms (e.g., OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbonatoms, hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1to 4 carbon atoms, dialkylamino wherein each alkyl group independentlyhas 1 to 4 carbon atoms, Ar or Het; R₄ is H, F, Cl, Br, I, OH, CN,nitro, NH₂, alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1to 4 carbon atoms (e.g., CF₃), cycloalkyl having 3 to 7 carbon atoms,cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbonatoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon atoms,cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4carbon atoms (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms(e.g., OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms,hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4carbon atoms, dialkylamino wherein each alkyl group independently has 1to 4 carbon atoms, Ar or Het; R₅ is H, F, Cl, Br, I, OH, CN, nitro, NH₂,alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbonatoms (e.g., CF₃), cycloalkyl having 3 to 7 carbon atoms,cycloalkylalkyl having 4 to 7 carbon atoms, alkoxy having 1 to 4 carbonatoms (e.g., OCH₃), cycloalkoxy having 3 to 7 carbon atoms,cycloalkylalkoxy having 4 to 7 carbon atoms, alkylthio having 1 to 4carbon atoms (e.g., SCH₃), fluorinated alkoxy having 1 to 4 carbon atoms(e.g., OCF₃, OCHF₂), hydroxyalkyl having 1 to 4 carbon atoms,hydroxyalkoxy having 2 to 4 carbon atoms, monoalkylamino having 1 to 4carbon atoms, dialkylamino wherein each alkyl group independently has 1to 4 carbon atoms, Ar or Het; Ar is an aryl group containing 6 to 10carbon atoms which is unsubstituted or substituted one or more times byalkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8 carbon atoms,halogen (F, Cl, Br, or I, preferably F or Cl), dialkylamino wherein thealkyl portions each have 1 to 8 carbon atoms, amino, cyano, hydroxyl,nitro, halogenated alkyl having 1 to 8 carbon atoms, halogenated alkoxyhaving 1 to 8 carbon atoms, hydroxyalkyl having 1 to 8 carbon atoms,hydroxyalkoxy having 2 to 8 carbon atoms, alkenyloxy having 3 to 8carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulphinylhaving 1 to 8 carbon atoms, alkylsulphonyl having 1 to 8 carbon atoms,monoalkylamino having 1 to 8 carbon atoms, cycloalkylamino wherein thecycloalkyl group has 3 to 7 carbon atoms and is optionally substituted,aryloxy wherein the aryl portion contains 6 to 10 carbon atoms (e.g.,phenyl, naphthyl, biphenyl) and is optionally substituted, arylthiowherein the aryl portion contains 6 to 10 carbon atoms (e.g., phenyl,naphthyl, biphenyl) and is optionally substituted, cycloalkyloxy whereinthe cycloalkyl group has 3 to 7 carbon atoms and is optionallysubstituted, sulfo, sulfonylamino, acylamido (e.g., acetamido), acyloxy(e.g., acetoxy) or combinations thereof; and Het is a heterocyclicgroup, which is fully saturated, partially saturated or fullyunsaturated, having 5 to 10 ring atoms in which at least 1 ring atom isa N, O or S atom, which is unsubstituted or substituted one or moretimes by halogen (F, Cl, Br, or I, preferably F or Cl), aryl having 6 to10 carbon atoms (e.g., phenyl, naphthyl, biphenyl) and is optionallysubstituted, alkyl having 1 to 8 carbon atoms, alkoxy having 1 to 8carbon atoms, cyano, trifluoromethyl, nitro, oxo, amino, monoalkylaminohaving 1 to 8 carbon atoms, dialkylamino wherein each alkyl group has 1to 8 carbon atoms, or combinations thereof; and pharmaceuticallyacceptable salts thereof.

Compounds corresponding to formulae (ix)(a), (ix)(b), (ix)(c), and(ix)(d) are described in further detail in U.S. Pat. No. 7,429,664(which is hereby incorporated by reference herein in its entirety)

In general, for the compounds of formulae (i), (ii), (iii), (iv), (v),(vi), (vii), (viii), and (ix)(a-d), definitions for the chemicalmoieties recited in the various substituent groups are the same as thosefound in the patent or published application cited above in connectionwith the formulae. Also, with regard to stereoisomers, it should beunderstood that a solid line designation for the bonds in thecompositions corresponding to formulae (i), (ii), (iii), (iv), (v),(vi), (vii), (viii), and (ix)(a-d) (and any others herein) forattachment of an substituent group to a chiral carbon atom of thecompound indicates that these groups may lie either below or above theplane of the page (i.e.,

or

). All isomeric forms of the compounds disclosed herein arecontemplated, including racemates, racemic mixtures, and individualenantiomers or diastereomers.

Another compound that may be used in the methods described herein isanabaseine, i.e., 2-(3-pyridyl)-3,4,5,6-tetrahydropyridine which is anaturally occurring toxin in certain marine worms (nemertine worms) andants (see, e.g., Kem et al., Toxicon, 9:23, 1971) and is a potentactivator of mammalian nicotinic receptors (see, e.g., Kem, Amer.Zoologist, 25, 99, 1985). Certain anabaseine analogs may also beemployed, such as DMAB(3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2′,3′-bipyridin-e)(see, e.g., U.S. Pat. No. 5,602,257 and WO 92/15306 (each of which ishereby incorporated by reference herein), and(E-3-[2,4-dimethoxy-benzylidene]-anabasine, also known as GTS-21 andDMXB (see, e.g., U.S. Pat. No. 5,741,802 and U.S. Pat. No. 5,977,144(each of which is hereby incorporated by reference herein in itsentirety). Another compound that may be used tropisetron, i.e., 1αH,5αH-tropan-3α-yl indole-3-carboxylate (see J. E. Macor et al., Bioorg.Med. Chem. Lett. 2001, 319-321).

Still other compounds having nicotinic acetylcholine receptor activitythat may be used in the methods of the present disclosure include, forinstance, U.S. Published Patent Application No. 2002/00288809; U.S.Published Patent Application No. 2009/0012127; U.S. Pat. No. 6,303,638;U.S. Pat. No. 6,846,817; U.S. Pat. No. 7,244,745; and U.S. Pat. No.7,429,664 (each of which is hereby incorporated by reference herein).

Improving Ataxia and Non-Ataxic Imbalance

Also provided are methods for improving a symptom selected from ataxiaand non-ataxic imbalance, or combinations thereof, in a patient. Ingeneral, the methods comprise administering to a patient exhibiting thesymptom(s) a compound having nicotinic acetylcholine receptor activity,such as those described above. In one embodiment, the compound isselected from the group consisting of ABT-089, ABT-894,alpha-bungarotoxin, anabaseine, bupropion, buspirone, BW284c51,cytisine, dihydro-beta-erythoidine, DMXB, DMXB-A (GTS-21), diazoxon,donepezil, exelon, fluoxetine, galantamine, huperzine A, ispronicline(TC-1734/AZD-3480), lobeline, mecamylamine, MEM3454, MEM63908,methyllycaconitine, nefazodone, octanol/ethanol, OmIA, paroxetine,sertraline, tacrine, TC-2559, TC-5214 ((S)-(+)-mecamylamine), TC-5619,tebanicline (ABT-594), varenicline, venlafaxine, XY4083, andcombinations thereof. In one another embodiment, the compound isselected from the group consisting of ABT-089, ABT-894, bupropion,cytisine, dianicline (SSR591813), DMXB-A (GTS-21), ispronicline(TC-1734/AZD-3480), lobeline, mecamylamine, methyllycaconitine, TC-2559,TC-5214 ((S)-(+)-mecamylamine), tebanicline (ABT-594), varenicline, andcombinations thereof. In another embodiment, the compound is selectedfrom the group consisting of donepezil, exelon, fluoxetine, galantamine,huperzine A, MEM3454, MEM63908, tacrine, XY4083, and combinationsthereof. In one preferred embodiment, the compound is varenicline.

Generally, the methods involve first diagnosing or assessing the levelof the ataxic or other symptom in the patient to provide a baselinelevel or measurement of the symptom (e.g., by virtue of its severity orintensity). Thereafter, the patient is administered (i.e., is treatedwith) a compound having nicotinic acetylcholine receptor activity,typically in the form of a pharmaceutical composition comprising thecompound and a pharmaceutically acceptable carrier.

At some point during or after administration of the compound (e.g., 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours,12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours, or longer(e.g., weeks, months, etc.), the patient's symptoms are again diagnosedor assessed. That is, a second measurement or level of the symptoms istaken; this measurement may be designated as a midpoint level or anendpoint level, depending on whether or not more treatments (i.e.,further administrations of the compound) and/or symptom assessments arecontemplated. The second (or subsequent) measurement may be compared tothe baseline measurement to evaluate the efficacy of the treatment.Preferably, the second (or subsequent) measurement (as a midpoint orendpoint) taken after administration of the compound is improvedrelative to the baseline measurement.

This treatment and assessment regime may be repeated as many times asdesired, with second, third, fourth, fifth, and so on, measurementsbeing compared to the original baseline measurement taken prior toadministration of the compound or otherwise initiating treatment.Assessments can be taken while the patient is still on a treatmentregime (i.e., during the period of time that the patient is given thecompound and while it is present in their system), and assessments mayalso be taken after a patient has stopped treatment and/or aftercomplete washout or elimination of the compound from the patient'ssystem.

Various scales can assess symptoms of ataxia and non-ataxic imbalance ina patient and the effect of the compounds described herein on thetreatment of the symptom. These are, for example, and withoutlimitation, the Scale for the Assessment and Rating of Ataxia (SARA),Friedreich's Ataxia Rating Scale (FARS), International CooperativeAtaxia Rating Scale (ICARS), Pourcher and Barbeau Ataxia Clinical RatingScale, the Unified Multiple System Atrophy Rating Scale (UMSARS), andthe like. The SARA, for example, is described by Schmitz-Hubsch et al.,Neurology 66, 1717-1720 (2006). The FARS, for example, is described inLynch et al., Neurology 2006; 66:1711-1716. The ICARS, for example, isdescribed in Trouillas et al., J. Neurological Sciences 1997;145(2):205-211. The Pourcher and Barbeau scale is described, forexample, in Leone et al., Ital. J. of Neurological Sciences 1986;7(1):61-62. Some of these and other ratings scales are described inHerndon, Handbook of Neurologic Rating Scales (2nd ed. 2006).

These scales or measures generally are carried out by observing thepatient (e.g., watching the patient perform or attempt to performcertain tasks) and assigning a score based on the intensity or frequencyof the symptoms and the ability, partial ability, or inability of thepatient to perform various tasks. The scales may also target or focusupon improvements in symptoms since a previous assessment. In certainembodiments, a total or overall score on the assessment or scale iscalculated. If desired, multiple scales or tests can be administered andtheir results combined. Typically, a baseline score is compared to asecond, subsequent (midpoint or endpoint) score to determine the changein severity or frequency of ataxia or non-ataxic imbalance aftertreatment with the compound(s) described herein.

Once the compound has been administered, a patient's symptoms may remainimproved relative to the baseline level, even after treatment has ceasedand no further administrations of the compound a performed. Thepatient's symptoms may remain at an improved level, for example, for 1day, 3 days, 5 days, 7 days, 3 weeks, 1 month, 3 months, 6 months, 1year, or longer, after the final administration of the compound. In thisregard, the methods described herein can be said to beneficially alterthe chemical and/or biochemical pathways of the patient.

Administration and Mode of Treatment

In general, where the pharmaceutical agents discussed above areadministered to a patient in need of treatment of one or more of thesymptoms noted above, the agent is administered in an effective amount;that is, an amount to achieve a therapeutic benefit.

In general, the compound having nicotinic acetylcholine receptoractivity is administered to the patient in the form of a pharmaceuticalcomposition or pharmaceutical formulation comprising the compound. Thecompositions or formulations generally comprise at least one activepharmaceutical ingredient having nicotinic acetylcholine receptoractivity and a pharmaceutically acceptable carrier (discussed in furtherdetail below). The structure and synthesis of many nicotinicacetylcholine receptor-active compounds are well known to persons ofskill in the art. A description of several representative compounds isprovided above, and may also be found in the patent and otherliterature. This includes, for example, the patents and publishedapplications cited herein, each of which is hereby incorporated byreference herein in its entirety.

The dose or amount of the pharmaceutical agent administered to thepatient should be an effective amount for the intended purpose; i.e.,treatment of one or more of the symptoms discussed above. Generallyspeaking, the effective amount of the agent administered to the patientcan vary according to a variety of factors such as, for example, theage, weight, sex, diet, route of administration, and the medicalcondition of the patient. Specifically preferred doses are discussedmore fully below, or are provided on the label of the pharmaceuticalagent(s) being administered, or is within the ambit of one skilled inthe art. It will be understood that the total daily usage of thecompounds discussed herein will be decided by the attending physicianwithin the scope of sound medical judgment.

The specific therapeutically effective dose level for any particularpatient will depend upon a variety of factors including the disease,pathological disorder, or medical condition of the patient, and theparticular symptoms being treated and the severity of the same; activityof the specific composition(s) employed; the age, body weight, generalhealth, sex and diet of the patient; the time of administration; theroute of administration; the rate of excretion of the specificcomposition(s) employed; the duration of the treatment; drugs used incombination or coincidental with the specific composition(s) employedand like factors are well known in the medical arts. For example, it iswell within the skill of the art to start doses of the compositions(s)at levels lower than those required to achieve the desired effect, andto gradually increase the dosage until the desired effect is achieved.By way of another example, the dose level can be gradually or abruptlydecreased to minimize undesired side effects of the compound beingadministered. If desired, the effective daily doses may be divided intomultiple doses for purposes of administration. Consequently, single dosecompositions may contain such amounts or submultiples to make up thedaily dose.

Administration of the pharmaceutical agent can occur as a single eventor over a time course of treatment. For example, one or more of thecompositions can be administered hourly (e.g., every hour, every twohours, every three hours, every four hours, every five hours, every sixhours, and so on), daily, weekly, bi-weekly, or monthly. For treatmentof acute conditions, the time course of treatment may be at leastseveral hours or days. Certain conditions could extend treatment fromseveral days to several weeks. For example, treatment could extend overone week, two weeks, or three weeks. For more chronic conditions,treatment could extend from several weeks to several months, a year ormore, or the lifetime of the patient in need of such treatment.Alternatively, the compositions can be administered hourly, daily,weekly, bi-weekly, or monthly, for a period of several weeks, months,years, or over the lifetime of the patient. The pharmaceuticalcompositions may be administered to a patient on an empty stomach, oradministered along with (i.e., before, during, or after) meals.

Dosage levels for the active agents are generally those indicated on thelabel of the pharmaceutical. One or more of the compounds may beutilized in a pharmaceutically acceptable carrier, additive or excipientat a suitable dose level ranging, for example, from about 0.05 to about200 mg/kg of body weight per day, preferably within the range of about0.1 to 100 mg/kg/day, most preferably in the range of 0.25 to 50mg/kg/day. As noted above, the desired dose may conveniently bepresented in a single dose or as divided doses administered atappropriate intervals, for example as two, three, four or more sub-dosesper day.

Ideally, the active ingredient should be administered to achieveeffective peak plasma concentrations of the active compound within therange of from about 0.05 uM to about 5 uM. Oral dosages, whereapplicable, will depend on the bioavailability of the compositions fromthe GI tract, as well as the pharmacokinetics of the compositions to beadministered. For intravenous use, these concentrations may be achieved,for example, by the intravenous injection of about a 0.05 to 10%solution of the active ingredient, optionally in saline, or orallyadministered as a bolus containing about 1 mg to about 5 g, preferablyabout 5 mg to about 500 mg of the active ingredient, depending upon theactive compound and its intended target. Desirable blood levels may bemaintained by a continuous infusion to preferably provide about 0.01mg/kg/hour to about 2.0 mg/kg/hour or by intermittent infusionscontaining about 0.05 mg/kg to about 15 mg/kg of the active ingredient.Likewise, continuous (e.g., hourly or daily) oral administration may bedesired or necessary. While it is possible that, for use in therapy, oneor more compositions of the invention may be administered as the rawchemical, it is preferable to present the active ingredient as apharmaceutical formulation, presented in combination with apharmaceutically acceptable carrier, excipient, or additive.

As noted above, the above-described compounds are generally dispersed ina pharmaceutically acceptable carrier prior to administration to thepatient. The carrier, also known in the art as an excipient, vehicle,auxiliary, adjuvant, or diluent, is typically a substance which ispharmaceutically inert, confers a suitable consistency or form to thecomposition, and does not diminish the efficacy of the compound. Thecarrier is generally considered to be “pharmaceutically orpharmacologically acceptable” if it does not produce an unacceptablyadverse, allergic or other untoward reaction when administered to apatient, especially a human.

The selection of a pharmaceutically acceptable carrier will also, inpart, be a function of the route of administration. In general, thecompositions can be formulated for any route of administration so longas the blood circulation system is available via that route. Forexample, suitable routes of administration include, but are not limitedto, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous,rectal, subcutaneous, intramuscular, intraorbital, intracapsular,intraspinal, intraperitoneal, or intrasternal), topical (nasal,transdermal, intraocular), intravesical, intrathecal, enteral,pulmonary, intralymphatic, intracavital, vaginal, transurethral,intradermal, aural, intramammary, buccal, orthotopic, intratracheal,intralesional, percutaneous, endoscopical, transmucosal, sublingual andintestinal administration. Typically, the route of administration isoral.

Pharmaceutically acceptable carriers for use in combination with thecompounds described herein are well known to those of ordinary skill inthe art and are selected based upon a number of factors: the particularcompound used, and its concentration, stability and intendedbioavailability; the subject, its age, size and general condition; andthe route of administration. Suitable nonaqueous,pharmaceutically-acceptable polar solvents include, but are not limitedto, alcohols (e.g., α-glycerol formal, β-glycerol formal,1,3-butyleneglycol, aliphatic or aromatic alcohols having 2 to 30 carbonatoms such as methanol, ethanol, propanol, isopropanol, butanol,t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin(glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, laurylalcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fattyalcohols such as polyalkylene glycols (e.g., polypropylene glycol,polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g.,dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide,N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide amides,2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone);esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esterssuch as monoacetin, diacetin, and triacetin, aliphatic or aromaticesters such as ethyl caprylate or octanoate, alkyl oleate, benzylbenzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerinsuch as mono, di-, or tri-glyceryl citrates or tartrates, ethylbenzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate,fatty acid esters of sorbitan, fatty acid derived PEG esters, glycerylmonostearate, glyceride esters such as mono, di-, or tri-glycerides,fatty acid esters such as isopropyl myristrate, fatty acid derived PEGesters such as PEG-hydroxyoleate and PEG-hydroxystearate,N-methylpyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleicpolyesters such as poly(ethoxylated)₃₀₋₆₀ sorbitol poly(oleate)₂₋₄,poly(oxyethylene)₁₅₋₂₀ monooleate, poly(oxyethylene)₁₅₋₂₀ mono12-hydroxystearate, and poly(oxyethylene)₁₅₋₂₀ mono ricinoleate,polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitanmonooleate, polyoxyethylene-sorbitan monopalmitate,polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitanmonostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas,Wilmington, Del., polyvinylpyrrolidone, alkyleneoxy modified fatty acidesters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylatedcastor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution),saccharide fatty acid esters (i.e., the condensation product of amonosaccharide (e.g., pentoses such as ribose, ribulose, arabinose,xylose, lyxose and xylulose, hexoses such as glucose, fructose,galactose, mannose and sorbose, trioses, tetroses, heptoses, andoctoses), disaccharide (e.g., sucrose, maltose, lactose and trehalose)or oligosaccharide or mixture thereof with a C₄ to C₂₂ fatty acid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid, lauricacid, myristic acid, palmitic acid and stearic acid, and unsaturatedfatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucicacid and linoleic acid)), or steroidal esters); alkyl, aryl, or cyclicethers having 2 to 30 carbon atoms (e.g., diethyl ether,tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethylether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycolether); ketones having 3 to 30 carbon atoms (e.g., acetone, methyl ethylketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatichydrocarbons having 4 to 30 carbon atoms (e.g., benzene, cyclohexane,dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane,sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene,dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral,vegetable, animal, essential or synthetic origin (e.g., mineral oilssuch as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons,mixed aliphatic and aromatic based hydrocarbons, and refined paraffinoil, vegetable oils such as linseed, tung, safflower, soybean, castor,cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ,sesame, persic and peanut oil and glycerides such as mono-, di- ortriglycerides, animal oils such as fish, marine, sperm, cod-liver,haliver, squalene, squalane, and shark liver oil, oleic oils, andpolyoxyethylated castor oil); alkyl or aryl halides having 1 to 30carbon atoms and optionally more than one halogen substituent; methylenechloride; monoethanolamine; petroleum benzin; trolamine; omega-3polyunsaturated fatty acids (e.g., alpha-linolenic acid,eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid);polyglycol ester of 12-hydroxystearic acid and polyethylene glycol(Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethyleneglycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

Other pharmaceutically acceptable solvents for use in formulations arewell known to those of ordinary skill in the art, and are identified inThe Chemotherapy Source Book (Williams & Wilkens Publishing), TheHandbook of Pharmaceutical Excipients, (American PharmaceuticalAssociation, Washington, D.C., and The Pharmaceutical Society of GreatBritain, London, England, 1968), Modern Pharmaceutics, (G. Banker etal., eds., 3d ed.) (Marcel Dekker, Inc., New York, N.Y., 1995), ThePharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw HillPublishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.)(Marcel Dekker, Inc., New York, N.Y., 1980), Remington's PharmaceuticalSciences (A. Gennaro, ed., 19th ed.) (Mack Publishing, Easton, Pa.,1995), The United States Pharmacopeia 24, The National Formulary 19,(National Publishing, Philadelphia, Pa., 2000), and A. J. Spiegel etal., Use of Nonaqueous Solvents in Parenteral Products, Journal ofPharmaceutical Sciences, Vol. 52, No. 10, pp. 917-927 (1963).

Formulations containing the active agents described above may take theform of solid, semi-solid, lyophilized powder, or liquid dosage formssuch as, for instance, aerosols, capsules, creams, emulsions, foams,gels/jellies, lotions, ointments, pastes, powders, soaps, solutions,sprays, suppositories, suspensions, sustained-release formulations,tablets, tinctures, transdermal patches, and the like, preferably inunit dosage forms suitable for simple administration of precise dosages.Typically, the active agent is administered in tablet or pill form,including, for example, soft chewable tablets, hard chewable tablets,and hard swallowable tablets; various sizes and shapes of tablets may beformed, generally by varying the size and shape of the die and punch.Representative tablet shapes include briquette, circular (i.e.,cylindrical), lozenge, and pillow shapes. The size and shape of thetablet may depend, in part, on the various components in the tablet andtheir amounts relative to other components in the tablet.

EXAMPLES

The following non-limiting examples are provided to further illustratethe present invention. It should be appreciated by those of skill in theart that the techniques disclosed in the examples that follow representapproaches the inventors have found function well in the practice of theinvention, and thus can be considered to constitute examples of modesfor its practice. However, those of skill in the art should, in light ofthe present disclosure, appreciate that many changes can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention.

OBJECTIVE: To assess the preliminary efficacy of varenicline (Chantix®)in treating cerebellar symptoms of spinocerebellar ataxia (SCA) andFragile-X-Associated Tremor Ataxia Syndrome (FXTAS).

BACKGROUND: Varenicline, a partial agonist at nicotinic 42 receptors,may improve cerebellar symptoms in SCA (Example 2) and in FXTAS (Example1).

DESIGN/METHODS: Seven patients from an academic movement disorderscenter with spinocerebellar ataxia (n=6) and FXTAS (n=1), were treatedwith open-label varenicline 1 mg twice daily. Two patients hadgenetically confirmed SCA 3, 1 patient had genetically confirmed SCA 6,3 patients had sporadic cerebellar ataxia with no family history, and 1patient had genetically-confirmed FXTAS. Patients were treated for 4weeks with varenicline, which was discontinued on day 30. They wereassessed at baseline and after 4 weeks using the Scale for theAssessment and Rating of Ataxia (SARA) (Schmitz-Hubsch et al, 2006) andthe Clinical Global Impression (CGI) scale. Ataxia experts blindlyassessed videotapes of the patients. RESULTS: Two patients (one with SCA6 and one with sporadic ataxia) discontinued varenicline due to flu-likesymptoms and increased tremor. In the remaining 5 patients, there was amean improvement of 2.4 points in gait scores and of 5 points for thetotal SARA scores with varenicline use. Three patients had markedimprovement, and 2 had moderate improvement in gait with varenicline useas measured by the CGI. Two of the patients who had marked improvementin gait with varenicline were smokers, and reduced their intake ofcigarettes by 50% while taking varenicline.

CONCLUSIONS/RELEVANCE: Varenicline was shown to effectively treatcerebellar symptoms in this blinded video analysis of ataxic patients.Further controlled studies are warranted to investigate the effect ofvarenicline and smoking on cerebellar symptoms.

Example 1

The Fragile X-associated Tremor Ataxia syndrome (FXTAS) is aneurodegenerative disorder that occurs in adult males over the age 50who are carriers of the fragile x mental retardation 1 (FMR-1)premutation. FXTAS symptoms include intention and postural tremor,ataxia, cognitive decline, parkinsonism, and autonomic dysfunction (1).Currently, there is no effective treatment for ataxia. We report thecase of a man with FXTAS whose ataxia and imbalance were greatlyimproved after starting varenicline in an effort to stop smoking.Discontinuation of varenicline resulted in a worsening of the gaitataxia. Open-label resumption of varenicline has led to a sustainedresponse of five months.

The patient was a 64-year old man with a nine-year history of posturaland intention tremor of his arms and a four-year history of gait ataxia.His symptoms became disabling in the past year with frequent fallsdespite the intermittent use of a walker. His tremor along withprogressive dysarthria and memory loss had significantly impairedactivities of daily living for one year.

The patient was identified by a known pedigree in which the patient'sgranddaughter and grandson (born to his daughter) have Fragile Xsyndrome (>200 CGG repeats in the FMR1 gene). He was subsequentlydiagnosed with FXTAS, on the basis of the FMR1 premutation (90 CGGtrinucleotide repeats) and published clinical criteria (1). His maternalaunt and his mother were premutation carriers, and two of his fourbrothers had postural and intention tremor and gait ataxia. His pastmedical history revealed he was treated for depression 35 years ago butwas otherwise non-contributory. He denied current depression. He smokedup to two packs of cigarettes per day for 50 years, drank one to twoalcoholic beverages per week but was never intoxicated. He was taking nomedications.

A timeline of the patient's clinical course is depicted in FIG. 1. Thepatient started varenicline one mg twice daily which helped him quitsmoking in a few days. One week after taking varenicline, he noted thathis walking improved and he no longer needed assistance from a walker toambulate. There was also marked improvement in his balance. The onlyside effect from varenicline was vivid dreaming, which occurred two daysafter starting it.

The patient was evaluated by the University of South Florida (USF)movement disorders center seven weeks after starting varenicline. Vitalsigns and physical examination were normal. His neurological examinationincluded a Mini Mental State Exam (MMSE) of 26/30, mild dysarthria, mildvoice tremor, severe postural and intention tremor of his arms, mildrigidity, and moderate dysmetria in all extremities. He was able to getout of a chair without assistance, and continued to walk six meters fivetimes (30 meters total) without rest or the assistance of a walker. Hewas able to tandem walk for two to three steps. The rest of hisneurological exam, including cranial nerves, reflexes, motor and sensoryexamination, was within normal limits. The patient received a score of 5(out of a maximum possible score=63) on a Beck's Depression Scale (BDI)(2). A magnetic resonance image (MRI) of the brain showedhyperintensities of the middle cerebellar peduncles typical of FXTASalong with cortical and cerebellar volume loss (FIG. 2). Chest X-ray wasclear, with no evidence of neoplasia.

The patient stopped varenicline seven weeks after starting it. Within 10days, he reported a slight worsening of the residual ataxia andimbalance. Within three weeks, he again needed a walker for ambulationand began to fall daily. The patient returned to clinic off varenicline.His vital signs and physical examination were normal, and hisneurological examination returned to the pre-varenicline state. He onceagain needed assistance to walk and was unable to tandem walk even withassistance. The rest of the neurological examination remained unchanged,including the postural and intention tremor. The BDI score had notchanged.

At week 11, the patient re-started varenicline one mg twice daily, andagain noted improvement in ataxia within one week. Due to vivid dreams,the varenicline dose was decreased to one mg daily at week 12. Thepatient has taken varenicline for 22 weeks, with a sustained ataxiaimprovement.

A videotape of the patient was scored by a blinded movement disordersexpert using the SARA (Scale for Assessment and Rating of Ataxia) (3).The SARA scores on varenicline one mg b.i.d. were “two” for functionalstaging for ataxia (ataxic symptoms were present and were recognized bypatient, but were still mild), “one” for tandem walking (the patient wasable to tandem walk in less than perfect manner or the patient couldtandem walk greater than four sequential steps but less than eightsteps) and “zero” for gait (normal). The SARA scores after the patienthad discontinued varenicline for three weeks included a “three” forfunctional staging for ataxia (ataxic symptoms considered overt andsignificant), “three” for tandem walking (the patient was considered toopoorly coordinated to attempt the task), and “two” for gait (the patientwalked with definite ataxia; may have needed intermittent support forwalking or the examiner needed to walk with patient for safety sake).

Varenicline is a highly selective partial agonist at the α4β2 nicotinicacetylcholine receptor that is approved by the FDA for smokingcessation. In this case report, a patient with FXTAS experienced markedimprovement in gait ataxia and imbalance while taking varenicline. Theclinical observations in this case are supported by a blinded rating ofvideotapes taken during and after varenicline use, and a re-emergence ofataxia and imbalance shortly after varenicline was discontinued.

Effective treatment of ataxia and imbalance is currently lacking. Caseseries and small controlled trials of several medications includingbuspirone, fluoxetine, zolpidem, and lamotrigine have demonstratedeither conflicting results or limited efficacy (4).

As noted above, recent reports suggest that selective activation of theα4β2 nicotinic acetylcholine receptor subtype may improve alcohol (10)and tetrahydrocannabinoid [Δ⁹THC]-induced ataxia in experimental animals(11). It is known that selective activation of α4β2 nicotinicacetylcholine receptors results in post-synaptic up-regulation (i.e.,desensitization) of dopamine receptors in the mesolimbic system (12,13).This may be relevant to tolerance and dependence, but it is unlikely toexplain the anti-ataxic effect of varenicline. Early evidence suggestsinstead that other neurotransmitters like glutamate can modulatenicotine-mediated attenuation of ethanol-induced ataxia (10). Inaddition, increased nitric oxide (NO) production followingintracerebellar injection of the α4β2 nicotinic acetylcholine receptorsagonist RJR-2403 may improve Δ⁹THC-induced ataxia via a mechanisms ofcross tolerance mediated through the powerful NO intracellular signalingsystem (11). These and other non-dopaminergic actions of vareniclineawait further investigation.

Because the patient stopped smoking at the same time varenicline wasstarted, it is plausible that smoking cessation led to gait improvement.However, this is unlikely, because there was a re-emergence of ataxiawhen varenicline was discontinued, although smoking had beendiscontinued several weeks before. The patient drank alcoholoccasionally, and the possibility that varenicline might have reducedalcohol-induced ataxia, rather than that solely caused by FXTAS, mustalso be entertained.

Further controlled studies on the effect of varenicline to improveataxia and imbalance are warranted. Caution is needed, as varenicline isassociated with potential risks of suicidal behavior, depressed mood,and agitation.

-   1. Jacquemont S, Hagerman R J, Leehey M, et al. Fragile X    premutation tremor/ataxia syndrome: molecular, clinical, and    neuroimaging correlates. Am J Hum Genet. 2003; 72(4):869-78.-   2. Beck A. T., Ward C., Mendelson M. (1961). “Beck Depression    Inventory (BDI)”. Arch Gen Psychiatry 4: 561-571.-   3. Schmitz-Hübsch T, du Montcel S T, Baliko L, et al. Scale for the    assessment and rating of ataxia: development of a new clinical    scale. Neurology. 2006 Jun. 13; 66(11):1717-20.-   4. Assadi M, Campellone J V, Janson C G, Veloski J J, Schwartzman R    J, Leone P. Treatment of spinocerebellar ataxia with buspirone. J    Neurol Sci. 2007 Sep. 15; 260(1-2):143-6.-   5. Falk L, Nordberg A, Seiger A, Kjaeldgaard A,    Hellstreöm-Lindahl E. Smoking during early pregnancy affects the    expression pattern of both nicotinic and muscarinic acetylcholine    receptors in human first trimester brainstem and cerebellum.    Neuroscience 2005; 132:389-397.-   6. Chen W J, Edwards R B, Romero R D, Parnell S E, Monk R J.    Long-term nicotine exposure reduces Purkinje cell number in the    adult rat cerebellar vermis. Neurotoxicol Teratol. 2003 May-June;    25(3):329-34.-   7. Chen W J A, Parnell S E, West J R. Nicotine decreases blood    alcohol concentration in neonatal rats. Alcohol Clin Exp Res 2001;    25:1072-1077.-   8. Pereira C B, Strupp M, Holzleitner T, Brandt T. Smoking and    balance: correlation of nicotine-induced nystagmus and postural body    sway. NeuroReport 2001; 8:1223-1226.-   9. Spillane J D. The effect of nicotine on spinocerebellar ataxia.    Br Med J 2: 1345, 1955. 1345-1351.-   10. Al-Rejaie S, Dar M S. Behavioral interaction between nicotine    and ethanol: possible modulation by mouse cerebellar glutamate.    Alcohol Clin Exp Res. 2006 July; 30(7):1223-33.-   11. Smith A D, Dar M S. Mouse cerebellar nicotinic-cholinergic    receptor modulation of Delta9-THC ataxia: role of the alpha4beta2    subtype. Brain Res. 2006 Oct. 18; 1115(1):16-25.-   12. Katz B, Thesleff A. A study of ‘desensitization’ produced by    actylcholine at the motor end plate. J Physiol 1967; 138:63-80.-   13. Arneric S P, Holladay M, Wiliams M. Neuronal nicotinic    receptors: A perspective on two decades of drug discovery research.    Biochemical Pharmacology 2007; 74:1092-1101.

Example 2

Spinocerebellar ataxia (SCA) is a group of inherited neurodegenerativedisorders characterized by progressive gait dysfunction, imbalance,impaired limb coordination, and altered speech. There is currently noeffective treatment for any of the SCA disorders. We report the cases of2 SCA patients (types 3 and 14) who experienced marked improvement intheir cerebellar symptoms, including ataxia and imbalance, while takingvarenicline (Chantix®, Pfizer, New York, N.Y.), a drug approved to aidsmoking cessation.

The first patient was a 63-year old woman with a 16-year history ofimbalance, gait dysfunction, and dysarthria who presented to an academicmovement disorders center for management of her symptoms. She had beendiagnosed with SCA type 3 twelve years ago by genetic testing, and had a3-generation history of SCA type 3. Her medical history included onemyocardial infarction 2 years ago, coronary artery disease,hypertension, and hyperlipidemia. The patient had a 50-pack year historyof smoking cigarettes.

On examination, the patient's vital signs and physical examination werenormal. Her neurologic examination included a Mini-Mental Status Exam(MMSE) of 30/30, mild dysarthria, mild to moderate postural andintention tremor, mild dystonia in her arms, mild akinesia, and moderatedysmetria in all extremities. Fast alternating hand movements wereirregular and marked by interruptions, and her heel to shin slide wasseverely abnormal bilaterally. Her gait was ataxic and dysmetric, andshe required the constant use of a walker or the support of a cane toambulate. Her cranial nerves and motor examination were normal, althoughthere was mild decrease in her sensory examination to light and deeptouch in a stocking-glove distribution. There was increased tone andhyperreflexia in her lower extremities. A recent magnetic resonanceimage (MRI) of the brain showed marked atrophy of the cerebellum.

After the evaluation, the patient started varenicline 0.5 mg twice dailyfor smoking cessation. The dose of varenicline was increased to 1 mgtwice daily after one week. Ten days after starting varenicline, thepatient reported that she had an improvement in depth perception, andthat her walking seemed easier and more stable. Twenty-one days afterfirst taking varenicline, the patient was able to walk for 3 blocksusing only a cane rather than a walker, with markedly improved balance.However, she did not stop smoking cigarettes at any time while takingvarenicline.

The patient returned to the academic movement disorders center one monthafter starting varenicline for routine follow-up. Her gait dysfunctionand akinesia improved markedly, and she was able to walk independentlywhile only occasionally reaching for the wall for stability. Limbdysmetria, fast alternating movements, finger to nose and heel-shinslide also markedly improved. A videotape of the patient was scored by ablinded movement disorders expert using the SARA (Scale for Assessmentand Rating of Ataxia) (1). The total SARA score prior to the patienttaking varenicline 1 mg twice daily was 29, while the score one monthafter starting varenicline was 13.

The second patient was a 51-year old woman who presented to an academicmovement disorders center for neurologic evaluation. After a 1-yearhistory of imbalance, incoordination, and speech disturbance, shereceived genetic testing that revealed mutations in the PRKCG gene,corresponding to the SCA14 locus on chromosome 19q13.4-qter. Thepatient's brother and father demonstrated symptoms of incoordination andclumsiness that were attributed to prior motor vehicle accidents,although neither had received genetic testing for SCA. The patient wasof German and Dutch ancestry. She had never smoked or used drugs oralcohol and had no allergies. Her medical history was significant forhypertension, which was treated with 325 mg of valsartan (Diovan). Priormedications to treat her cerebellar symptoms included levodopa/carbidopa(Sinemet), lorazepam (Ativan), clonazapem (Klonopin), and zolpidem(Ambien), to no avail.

On evaluation, the patient's vital signs and physical examination werenormal. Her neurologic examination included a Mini-Mental StatusExamination of 30/30, mild dysarthria, mild postural and intentiontremor, and moderate dysmetria in all extremities. Her gait consisted ofmoderate to severe ataxia, and she required the constant use of a walkeror the support of a cane to ambulate. The patient could tandem walk onlywith support. Increased tone and hyperreflexia were present in her lowerextremities, with occasional myoclonus of her right leg. A recentmagnetic resonance imaging of the brain showed cerebellar atrophy.

The patient was started on 0.5 mg of varenicline (Chantix®) once a day,titrating to 1 mg twice daily after 1 week with the understanding thatthis was being used as an off-label medication. She complained of nauseafor 7 days after taking the medication, but reported marked improvementsin walking, coordination, speech, and balance 8 days after startingvarenicline. The patient returned to the academic movement disorderscenter 3 weeks after starting varenicline. Her gait dysfunction improvedmarkedly so that she could walk without assistance. Other symptomsincluding speech, dysmetria, and finger-to-nose and heel-to-shinmaneuvers also markedly improved. The patient was scored by a blindedmovement disorders expert using the SARA. The patient's total SARA scorebefore taking 1 mg of varenicline twice daily was 22, whereas the score3 weeks after starting varenicline was 8. The patient remained onvarenicline for 8 weeks with continued efficacy but discontinued itowing to financial considerations. She was reexamined 4 weeks afterdiscontinuing varenicline, and her neurologic examination had returnedto prevarenicline status.

Varenicline is a highly selective partial agonist at α4β2 nicotinicacetylcholine receptors and a full agonist at α7 nicotinic acetylcholinereceptors (2). The exact mechanism of action for the beneficial effectof varenicline in these cases is unknown. It has been postulated thatnicotinic acetylcholine receptor subunits are involved in the modulatingcerebellar activity in humans (3). Nicotinic acetylcholine receptors α3,α4, α6, and α7 have been localized in Purkinje cell and granule celllayers in human autopsy specimens suggesting that these receptors arepresent in nerve terminals of the cerebellum (3). Further, selectiveactivation of the α4β2 nicotinic acetylcholine receptor subtype improvesalcohol (4) and tetrahydrocannabinoid [Δ⁹THC]-induced ataxia in animals(5).

There is no effective treatment of ataxia, and case series and smallcontrolled trials of several medications including antianxiolytics,antidepressants, and antiepileptics have shown limited efficacy or havebeen conflicting (6). Thus, controlled studies on the effect ofvarenicline on ataxia and imbalance are warranted. Adverse effects ofvarenicline include nausea, sleep disturbance, constipation, flatulence,and vomiting. Caution is needed in prescribing varenicline owing to itsrecent reports of suicidal behavior associated with its use.

-   1. Schmitz-Hübsch T, du Montcel S T, Baliko L, et al., Scale for the    assessment and rating of ataxia: development of a new clinical    scale. Neurology. 2006 Jun. 13; 66(11):1717-20.-   2. Mihalak K B, Carroll F I, Luetje C W, Varenicline is a partial    agonist at alpha4beta2 and a full agonist at alpha7 neuronal    nicotinic receptors. Mol. Pharmacol. 2006; 70(3):801-805.-   3. Graham A, Court J A, Martin-Ruiz C M et al., Immunohistochemical    localisation of nicotinic acetylcholine receptor subunits in human    cerebellum. Neuroscience 2002; 113(3):493-507.-   4. Al-Rejaie S, Dar M S, Behavioral interaction between nicotine and    ethanol: possible modulation by mouse cerebellar glutamate. Alcohol    Clin. Exp. Res. 2006; 30(7):1223-1233.-   5. Smith A D, Dar M S, Mouse cerebellar nicotinic-cholinergic    receptor modulation of Delta9-THC ataxia: role of the alpha4beta2    subtype. Brain Res. 2006; 1115(1):16-25.-   6. Chen W J, Edwards R B, Romero R D, et al., Long-term nicotine    exposure reduces Purkinje cell number in the adult rat cerebellar    vermis. Neurotoxicol Teratol 2003; 25(3):329-334.

What is claimed is:
 1. A method of treating the loss or failure ofmuscular coordination resulting from type 3 or type 14 Spinocerebellarataxia or fragile X/tremor ataxia syndrome in a human, the methodcomprising administering varenicline to the human.
 2. The method ofclaim 1 wherein the method is for treating ataxia resulting from type 3Spinocerebellar ataxia.
 3. The method of claim 1 wherein the method isfor treating ataxia resulting from type 14 Spinocerebellar ataxia. 4.The method of claim 1 wherein the method is for treating ataxiaresulting from fragile X/tremor ataxia syndrome.